Zhou Xinna, Wang Xiaoli, Song Qingkun, Yang Huabing, Zhu Xishan, Yu Jing, Song Guohong, Di Lijun, Ren Jun, Shao Hong, Lyerly Herbert Kim
Int J Clin Pharmacol Ther. 2015 Nov;53(11):914-22. doi: 10.5414/CP202391.
The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities.
93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded.
GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity.
These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.
基于药物分子特征，转移性乳腺癌（MBC）向二线化疗的转变被广泛要求以实现精准医学。癌症的新兴精准治疗需要实施明确的药物遗传学特征，以阐明对癌症化疗的预测反应。因此，我们感兴趣于分析谷胱甘肽S-转移酶pi 1基因（GSTP1）等位基因的单核苷酸多态性（SNP）的作用，以确定与临床反应和毒性预测指标的药理学联系。
93例接受噻替派加多西他赛化疗的MBC患者纳入本研究。主要选择优化的细胞色素P450 3A5（CYP3A5）、细胞色素P450 2B6（CYP2B6）和GSTP1作为候选基因，并通过基质辅助激光解吸电离/飞行时间（MALDI-TOF）质谱对其三个SNP（CYP2B6 G516T、CYP3A5 A6986G和GSTP1 A313G）进行基因分型。记录无进展生存期（PFS）、疾病控制率和化疗相关毒性。
GSTP1 A313G（rs1695）被确定与疾病进展相关。特别是，携带AG/GG基因型的患者的PFS在统计学上比携带AA基因型的患者更长。多变量分析证实AG/GG基因型与临床反应和肝局部转移灶均相关。这三个SNP与化疗诱导的毒性之间未发现相关性。
这些结果表明，GSTP1多态性是含噻替派化疗方案临床反应的一种新型预后标志物。此类证据可为药物遗传学在仅通过经验选择改变治疗方案时消除偏差的作用提供见解。
